The introduction of HIV antiretroviral medication (ARVs) in Africa has resulted in substantial reductions in morbidity and mortality. This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study (RCCS) in Uganda, the impact of ARVs on HIV transmission among HIV discordant couples, impact of immunologic monitoring, and potential delays in detecting virologic failure on transmitted and acquired genotypic ARV resistance. We have shown complete elimination of transmission among discordant couples on ARVs and continue to scale up treatment. We have continued to monitor the impact of combination prevention among high risk fishing communities bordering Lake Victoria. Average ART coverage among HIV-positive persons increased from 18.6% in 2011 to 69% by 2016, while MMC coverage among non-Muslim men increased from 24.3% to 59% over the same time period. HIV viral load suppression among all HIV-positive persons increased from 42% in 2009 to 75% by 2016. HIV incidence declined by 42% in 2016 relative to the period prior to 2010 before the scale-up of combination HIV prevention (1.17/100 py to 0.66/100 py; adjIRR=0.58; 95%CI: 0.45-0.76); declines were greater in men (adjIRR=0.46; 95%CI: 0.29-0.73) than women (adjIRR=0.68, 95%CI: 0.50-0.94).. Rapid scale-up of combination HIV prevention in high-risk fishing communities on Lake Victoria is feasible, and there is preliminary empirical evidence of the effects of these interventions in decreasing HIV incidence. We also assessed migration patterns using data collected between August 2011 and January 2015 from the RCCS. 29% (n=6718) of participants who migrated over 2 years were significantly more likely to be young and female. Compared to long-term residents, risk of HIV-infection was significantly elevated in women and men in the first two years following migration (women: adjIRR=1.92, 95%CI: 1.52-2.43; men: adjIRR=1.75, 95%CI: 1.33-2.33). While HIV incidence significantly declined among residents and non-recent in-migrants with scale-up of combination HIV prevention, it did not decline among recent in-migrants. HIV-infected migrants, largely women, are less likely to use ART and differentially move into hotspot fishing communities. However, migrants from these hotspots do not account for a substantial proportion of migrant-associated HIV infection elsewhere suggesting that test and treat targeted to hotspots may not abate the generalized epidemic. One concern with increased use of ARVs in sub-Saharan Africa is the extent by which viral resistance will develop over time among the non-clade B HIV-1-infected individuals. We measured the levels of transmitted antiretroviral drug resistance among 75 recently infected RCCS seroconverters with documented seroconversion between 2012 and 2013. We found low rates of transmitted antiretroviral drug resistance with only 3 individuals (4%) having resistance, 2 to NNRTIs, one had PI resistance and no resistance found to NRTIs. Viral load monitoring (VLM) is currently being scaled up in Uganda after a decade of relying on immunologic and clinical monitoring. We observed late switching to second line therapy to be a problem among 3,287 HIV-infected persons who initiated ART between 2004 and 2011, of whom 173 met the criteria for virologic failure 6 or more months after ART initiation. 121 (70%) switched to second line ART. The median timing of switching to second line ART was 7.8 months after virologic failure (IQR=3.3-15.2). Cumulative incidences of switching at 6, 12 and 24 months after virologic failure were 33.2% (95% CI=26.2 41.0), 49.8% (95% CI=42.3 57.9) and 71.9% (95% CI=64.2 79.2) respectively. We observed earlier switching to second line among patients with more advanced disease (lower CD4, higher VL) suggesting that clinicians were still relying on clinical and immunologic parameters. Patients not switched to second line therapy were significantly more likely to die, with an adjusted mortality of 11.1% compared to those switched at 1.6% (p-value==0.005). Among those switched, the longer the time interval between virologic failure and regimen switch, the more patients experienced CD4 decrease and/or further increase in VL during that interval.We have also examined the use of early VL monitoring to identify patients most at risk for long term success and failure on first line ART. The 12 month VL measurement was found to be highly predictive of long term outcomes, In adjusted analysis, compared to clients with <400 copies/ml at 12 months, the adjusted hazard ratios of VF were 6.54 (95% CI=2.7-15.9) in clients with VLs of 400-1000 copies/ml, 7.82 (95% CI=2.7-22.4) in clients with VLs of 1001-2000 copies/ml and 26.81 (95% CI=15.4-46.6) in clients with VLs greater than 2000 copies/ml (p-value<0.001). Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. Our study of Acyclovir suppressive therapy among HIV-1/HSV-2 co-infected patients showed an overall reduction in HIV-1 disease progression by 25% compared to placebo (p=0.04). In a sub-analysis stratified by baseline VL, participants with baseline HIV VL > 50 000 copies/ml treated with Acyclovir had a 38% reduced rate of disease progression compared to placebo (p=0.03). In a secondary analysis, we found that the rate of GUD and HSV-2 shedding doubled in the first 3 months after ARV initiation, returning to baseline by 6 months suggesting a possible IRIS effect. We found a similar increase among these same women when we measured vaginal CMV shedding. We assessed the humoral immune response to CMV among women in this trial to investigate any association with disease progression and immune activation. We found that the highest CMV IgG tertile at baseline was independently associated with the primary outcome (ART initiation or death) compared to the lowest CMV IgG tertile (adjusted Hazard Ratio=1.59 95%CI=1.05-2.39; P=0.027). Among pre-ART visits, log10 CMV IgG antibody levels were positively associated with soluble CD14 and log10 C-reactive protein levels (P<0.01). The humoral immune response to CMV was associated with HIV disease progression and immune activation. We also examined proinflammatory cytokine expression during herpes virus reactivation. Herpes simplex virus-2 shedding was significantly associated with higher levels of IL-6 (RR = 1.4, P = .003) and TNF- (RR = 1.3, P = .010), whereas CMV shedding was associated with higher IL-6 (RR = 1.3, P = .006) and IL-2 (RR = 1.4, P = .01). The association of viral shedding with higher IL-6 levels suggests that herpes virus reactivation may be playing a role in immune activation after ART initiation. Antiretroviral therapy (ART) may interfere with replication of hepatitis B (HBV) raising the hypothesis that HBV infection might be prevented by ART. We investigated the incidence and risk factors associated with HBV among HIV-infected adults in Rakai, Uganda. We screened stored sera from 944 HIV-infected adults enrolled in the Rakai Community Cohort Study between September 2003 and March 2015 for evidence of HBV exposure. Serum from participants who tested anti-HBc negative (497) at baseline were tested over 3-7 consecutive survey rounds for incident HBV. HBV incidence was 1.17/100 p-y and found to be significantly lower with ART use: (0.49 /100 p-y) with ART and (2.3/100 p-y) without ART aHR=0.25 (95% CI, 0.1-0.5) p<0.001, No new HBV infections occurred among those on tenofovir-based ART. HBV continues to be acquired in adulthood among HIV-positive Ugandans and HBV incidence is dramatically reduced with HBV-active ART. In addition to widespread vaccination, initiation of ART may prevent HBV acquisition among HIV-positive adults in sub-Saharan Africa.